Formulation containing anti-inflammatory androstane derivatives

ABSTRACT

There is provided according to the invention a pharmaceutical formulation comprising an aqueous carrier liquid having dissolved therein (a) an ester of fluticasone or a solvate thereof as medicament and (b) a solubilising agent for assisting the solubilisation of the medicament in the aqueous carrier liquid.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.10/066,951, filed 4 Feb. 2002, now allowed, which was aContinuation-in-part of U.S. patent application Ser. No. 09/958050 filedon 2 Oct. 2001, which was a 35 USC 371 National Phase Application ofInternational Patent Application No. PCT.GB01.03495 filed 3 Aug. 2001,which claims priority to United Kingdom Patent Application No. GB0019172.6 filed 5 Aug. 2000.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical formulationscontaining anti-inflammatory and anti-allergic compound of theandrostanes series and to processes for their preparation. The presentinvention also relates to therapeutic uses thereof, particularly for thetreatment of inflammatory and allergic conditions.

BACKGROUND OF THE INVENTION

Glucocorticoids which have anti-inflammatory properties are known andare widely used for the treatment of inflammatory disorders or diseasessuch as asthma and rhinitis. For example, U.S. Pat. No. 4,335,121discloses 6α,9α-Difluoro-17α-(1-oxopropoxy)-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester (known by the generic name of fluticasonepropionate) and derivatives thereof. The use of glucocorticoidsgenerally, and especially in children, has been limited in some quartersby concerns over potential side effects. The side effects that arefeared with glucocorticoids include suppression of theHypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth inchildren and on bone density in the elderly, ocular complications(cataract formation and glaucoma) and skin atrophy. Certainglucocorticoid compounds also have complex paths of metabolism whereinthe production of active metabolites may make the pharmacodynamics andpharmacokinetics of such compounds difficult to understand. Whilst themodern glucocorticoids are very much safer than those originallyintroduced, it remains an object of research to produce new moleculesand formulations of old and new molecules which have excellentanti-inflammatory properties, with predictable pharmacokinetic andpharmacodynamic properties, with an attractive side effect profile, andwith a convenient treatment regime.

We have now identified a novel glucocorticoid compound and formulationthereof which substantially meets these objectives. In particular wehave invented a novel formulation suitable for intranasal and alsoinhaled administration of a novel glucocorticoid compound and otheresters of fluticasone including fluticasone propionate.

Many millions of individuals suffer from seasonal and perennial allergicrhinitis worldwide. Symptoms of seasonal and perennial allergic rhinitisinclude nasal itch, congestion, runny nose, sneezing and watery eyes.Seasonal allergic rhinitis is commonly known as ‘hay fever’. It iscaused by allergens which are present in the air at specific times ofthe year, for example tree pollen during Spring and Summer. Perennialallergic rhinitis is caused by allergens which are present in theenvironment during the entire year, for example dust mites, mold, mildewand pet dander.

To formulate an effective pharmaceutical nasal composition, themedicament must be delivered readily to all portions of the nasalcavities (the target tissues) where it performs its pharmacologicalfunction. Additionally, the medicament should remain in contact with thetarget tissues for relatively long periods of time. The longer themedicament remains in contact with the target tissues, the medicamentmust be capable of resisting those forces in the nasal passages thatfunction to remove particles from the nose. Such forces, referred to as‘mucociliary clearance’, are recognised as being extremely effective inremoving particles from the nose in a rapid manner, for example, within10-30 minutes from the time the particles enter the nose.

Other desired characteristics of a nasal composition are that it mustnot contain ingredients which cause the user discomfort, that it hassatisfactory stability and shelf-life properties, and that it does notinclude constituents that are considered to be detrimental to theenvironment, for example ozone depletors. In the case of administrationof glucocorticoids, the potential for any undesirable side effectsshould preferably be minimised.

SUMMARY OF THE INVENTION

Thus, according to one aspect of the invention, there is provided apharmaceutical formulation comprising an aqueous carrier liquid havingdissolved therein (a) an ester of fluticasone or a solvate thereof asmedicament and (b) a solubilising agent for assisting the solubilisationof the medicament in the aqueous carrier liquid.

Preferably the ester of fluticasone is a compound of formula (I)

wherein R represents ethyl or a 5 membered heterocyclic aromatic ringcontaining 1 to 3 heteroatoms selected from O, N and S, optionallysubstituted by one or more methyl or halogen atoms or a solvate thereof.

Solvates of esters of fluticasone includes solvates withpharmaceutically acceptable solvents eg hydrates.

In a first embodiment of the invention, preferably R represents ethyland the compound of formula (I) is fluticasone propionate.

In a second embodiment of the process, preferably R representsfuran-2-yl and the compound of formula (I) has the chemical name: 6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Hitherto, nasal formulations of glucocorticoid compounds, particularlyaqueous formulations of glucocorticoid compounds, have been in the formof suspensions. In such suspension products the active ingredient issuspended in the aqueous carrier in the form of finely dividedparticles, typically of mass median diameter (MMD) 1-5 microns.Particles of this size are typically produced by micronisation, which isa wasteful and hazardous process.

Solution formulations have advantages in that the use of micronisationprocesses may be avoided and also in that onset of action may beincreased since it is not necessary for any dissolution process to takeplace before the drug enters the cells in which it acts and exerts itsanti-inflammatory effect. However fluticasone esters are quite insolublein water (typically less than 1 μg/ml) and so it might be thought thatthe large volumes of dilute liquid which would need to be administeredto have therapeutic effect would be impractical. We have nowsurprisingly discovered that the presence of a solubilising agent whichis preferably a surfactant, especially a surfactant selected from thegroup consising of aα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymer (also known as a octylphenoxypolyethoxyethanol) and a4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxiranesignificantly increases the solubility of fluticasone esters in waterthus permitting acceptably concentrated solutions to be developed. Thesolubility of fluticasone esters in water in the presence of such asurfactant is maximised when the formulation is prepared in a particularmanner as described later which forms a particular aspect of theinvention.

We have also surprisingly discovered that the solubility of fluticasoneesters can be increased yet further by dissolution in the aqueouscarrier liquid of a hydroxyl containing organic co-solvating agent or ofphosphatidiyl choline. Thus formulations including this additionalcomponent have further advantages and are preferred.

Examples ofα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymer surfactants include those of the Triton series eg Triton X-100,Triton X-114 and Triton X-305 in which the X number is broadlyindicative of the average number of ethoxy repeating units in thepolymer. For example the average number of ethoxy repeating units in aseries of Triton X surfactants is as follows: Triton Average number ofethoxy units X-45   5 X-114 7-8 X-100  9-10 X-102 12-13 X-165 16 X-30530 X-405 40 X-705 70

Preferably the number of repeating units in theα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymer is around 7-70, particularly around 7-30 especially around 7-10.

4-(1,1,3,3-Tetramethylbutyl)phenol polymers with formaldehyde and oxirantypically have a relative molecular weight of 3500-5000 especially4000-4700. An example structure is given below:

Thus as just noted, m may represent 6-8 eg 7 and n may represent 1-5,especially 3-5 eg 5. The preferred example is Tyloxapol.

Preferably the surfactant is Triton X-100 or Tyloxapol since thesesurfactants have the highest solubilising power and can therefore beemployed at the lowest concentrations. The most preferred surfactant isTyloxapol.

The solubility of fluticasone propionate in various surfactants in waterwith and without an organic co-solvating agent or phosphatidyl cholineis given in the following table: Surfactant Concentration (% w/w)Solubility (μg/ml) Triton X-100 2 69 Tyloxapol 2 41 Tyloxapol 5 133Tyloxapol and 5 197 Phospatidyl choline 1 Tyloxapol and 5 207 PEG200 10Labrasol 10 None detected Sodium 5 5.9 chenodesoxycholate Triton X-45 5None detected Sodium cholate 20 140 2 11 — — <1

Labrasol, sodium chenodesoxycholate, Triton X-45 and sodium cholate werenot considered suitable for use in formulations according to theinvention since excessively high concentrations of such surfactants areneeded to be used to dissolve the fluticasone ester to a sufficientextent.

The solubility in water of compound of formula (I) in which R representsfuran-2-yl in various surfactants is shown in the following table:Surfactant Concentration (% w/w) Solubility (μg/ml) Triton X-100 0.5 18″ 2 266 ″ 5 549 Triton X-100 and 5 840 PEG200 10 Tyloxapol 2 95 ″ 5 307″ 6 346 ″ 7.5 576 ″ 10 585 Triton X-305 5 204 — — <1

In formulations of the invention, the surfactant will typically beemployed in a concentration of around 0.5-10%, preferably around 2-5%w/w based on weight of formulation. The precise concentration chosenwill depend on the nature and concentration of the glucorticoid. Thesurfactant will need to be soluble in the formulation at theconcentration used.

Examples of hydroxyl containing organic co-solvating agents includeglycols such as polyethylene glycols (eg PEG 200) and propylene glycol;sugars such as dextrose; and ethanol. Dextrose and polyethylene glycol(eg PEG 200) are preferred, particularly dextrose. Propylene glycol ispreferably used in an amount of no more than 20%, especially no morethan 10% and is most preferably avoided altogether. Ethanol is alsopreferably avoided.

The hydroxyl containing organic co-solvating agents are typicallyemployed at a concentration of 1-20% eg 5-10%, eg around 5% w/w based onweight of formulation.

When phosphatidyl choline is employed it is typically employed at aconcentration of 0.1-10% eg 0.5-5%, eg around 1% w/w based on weight offormulation.

The effect of addition of a hydroxyl containing organic co-solvatingagent to solubility in water of compound of formula (I) in which Rrepresents furan-2-yl in various surfactants is shown in the followingtable: Surfactant/ co-solvating agent Concentration (% w/w) Solubility(μg/ml) Tyloxapol 5 344 Tyloxapol 5 836 PEG200 10 Tyloxapol 5 422Propylene glycol 10 Tyloxapol 5 526 Dextrose 4

The aqueous carrier liquid will essentially comprise water.

However for nasal administration it may also have dissolved in it one ormore of the following components:

-   -   viscosity enhancing agents.    -   preservatives.    -   isotonicity adjusting agents.

The formulations of the present invention may be stabilised byappropriate selection of pH using hydrochloric acid. Typically, the pHwill be adjusted to between 4.5 and 7.5, preferably between 5.0 and 7.0,especially around 6.5.

Examples of pharmaceutically acceptable materials which can be used toadjust the pH of the formulation include hydrochloric acid and sodiumhydroxide. Preferably, the pH of the formulation will be adjusted usinghydrochloric acid.

The aqueous component is preferably a high grade quality of water, mostpreferably purified water.

Examples of viscosity enhancing agents include carboxymethylcellulose,veegum, tragacanth, bentonite, hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, poloxamers (eg. poloxamer407), polyethylene glycols, alginates xanthym gums, carageenans andcarbopols. Preferably, the viscosity enhancing agent will be carboxymethylcellulose sodium.

Preferably, the viscosity enhancing agent will possess thixotropicproperties which will ensure that the formulation assumes a gel likeappearance at rest, characterised by a high viscosity value. Once thecomposition is subjected to shear forces, such as those caused byagitation prior to spraying, the viscosity of the formulation willpreferably decrease transiently to such a level to enable it to flowreadily through the spray device and exit as a fine mist spray. Thismist will then be capable of infiltrating the mucosal surfaces of theanterior regions of the nose (frontal nasal cavities), the frontalsinus, the maxillary sinuses and the turbinates which overlie theconchas of the nasal cavities. Once deposited, the viscosity of theformulation will preferably increase to a sufficient level to assume itsgel-like form and resist being cleared from the nasal passages by theinherent mucocillary forces that are present in the nasal cavities.

When the formulation of the present invention comprises a viscosityenhancing agent, it will be desirably added in a suitable amount toachieve this function, preferably the viscosity enhancing agent will bepresent within the formulation in an amount of between 0.1 and 5% (w/w),eg 1.5% (w/w), based on the total weight of the formulation.

For stability purposes, the formulation of the present invention shouldbe protected from microbial contamination and growth. Examples ofpharmaceutically acceptable anti-microbial agents that can be used inthe formulation include quaternary ammonium compounds (eg. benzalkoniumchloride, benzethonium chloride, cetrimide and cetylpyridiniumchloride), mercurial agents (eg. phenylmercuric nitrate, phenylmercuricacetate and thimerosal), alcoholic agents (eg. chlorobutanol,phenylethyl alcohol and benzyl alcohol), antibacterial esters (eg.esters of para-hydroxybenzoic acid), chelating agents such as disodiumedetate (EDTA) and other anti-microbial agents such as chlorhexidine,chlorocresol, sorbic acid and its salts and polymyxin.

Preferably, the preservative will comprise disodium edetate, which willpreferably be present within the formulation in an amount of between0.001 and 1% (w/w), especially around 0.015% (w/w), based on the totalweight of the formulation.

Preferably the preservative will comprise potassium sorbate which willpreferably be present within the formultaion in an amount of between0.01 and 1% (w/w), especially around 0.015% (w/w) based on the totalweight of the formulation.

Preferably, the preservative will comprise benzalkonium chloride (BKC),which will preferably be present within the formulation in an amount ofbetween 0.001 and 1% (w/w), especially around 0.015% (w/w), based on thetotal weight of the formulation.

More preferably, the preservative comprises disodium edetate andbenzalkonium chloride.

The presence of an isotonicity adjusting agent is to achieve isotonicitywith body fluids eg fluids of the nasal cavity, resulting in reducedlevels of irritancy associated with many nasal formulations. Examples ofsuitable isotonicity adjusting agents are sodium chloride, dextrose andcalcium chloride. Preferably, the isotonicity adjusting agent will bedextrose, most preferably used as dextrose anhydrous.

When the formulation of the present invention comprises an isotonicityadjusting agent it will be desirably added in a sufficient quantity toachieve this function, preferably the isotonicity adjusting agent willbe present within the formulation in an amount of between 0.1 and 10%(w/w), especially 5.0% w/w, based on the total weight of theformulation.

Fluticasone esters eg the compounds of formula (I), especially when Rrepresents furan-2-yl, and formulations thereof have potentiallybeneficial anti-inflammatory or anti-allergic effects, particularly upontopical administration to the nose, demonstrated by, for example, itsability to bind to the glucocorticoid receptor and to illicit a responsevia that receptor, with long acting effect. Hence, formulationsaccording to the invention are useful in the treatment of inflammatoryand/or allergic disorders of the nose, especially in once-per-daytherapy.

Formulations according to the invention may be prepared by dissolvingthe ingredients in water. If necessary the pH may be adjusted as a finalstep. Generally it will be desirable to filter the solution to removeany residual particulate matter. Formulations so prepared may then befilled into the receptacle.

We have however invented an improved process for preparing formulationsaccording to the invention which comprises:

-   -   (a) dissolving the fluticasone ester in the undiluted surfactant        at an elevated temperature (typically 60-70° C.);    -   (b) adding hot water (typically 60-70° C.) together with other        formulation ingredients to achieve the desired concentration of        active ingredient;    -   (c) if desired modifying the pH of the final solution;    -   (d) filtering the hot solution to remove any residual        particulate matter.

Preferably the temperature of the liquids in steps (a) and (b) and thetemperature of the liquid filtered in step (c) is 45° C. or greater,preferably 55° C. or greater, especially 65° C. or greater. Thetemperature is preferably 80° C. or less, eg 70° C. or less.

As noted above, this improved process permits solutions of higherconcentration to be prepared than is possible by conventionaltechniques. For example this process performed at 60-70° C. increasesthe solubility of fluticasone propionate from 87 to 133 μg/ml in 5%Tyloxapol and the compound of of formula (I) when R representsfuran-2-yl from 233 to 344 μg/ml in 5% Tyloxapol relative to the processperformed at room temperature.

Aqueous formulations of the invention may also be employed for rectal,aural, otic, oral, topical or parenteral administration oradministration by inhalation for the treatment of other localinflammatory conditions (eg dermatitis, asthma, chronic obstructivepulmonary disease (COPD) and the like). For example formulations of theinvention may be administered to the lung by nebulisation. Suchformulations may employ excipients (eg preservatives, buffers and thelike) appropriate for the route of administration.

The particularly desirable biological properties of the compound offormula (I) wherein R represents furan-2-yl are now explained below:

Compound (I) wherein R represents furan-2-yl undergoes highly efficienthepatic metabolism to yield the 17-β carboxylic acid (X) as the solemajor metabolite in rat and human in vitro systems. This metabolite hasbeen synthesised and demonstrated to be >1000 fold less active than theparent compound in in vitro functional glucocorticoid assays.

This efficient hepatic metabolism is reflected by in vivo data in therat, which have demonstrated plasma clearance at a rate approachinghepatic blood flow and an oral bioavailability of <1%, consistent withextensive first-pass metabolism.

In vitro metabolism studies in human hepatocytes have demonstrated thatcompound (I) is metabolised in an identical manner to fluticasonepropionate but that conversion of (I) to the inactive acid metaboliteoccurs approximately 5-fold more rapidly than with fluticasonepropionate. This very efficient hepatic inactivation would be expectedto minimise systemic exposure in man leading to an improved safetyprofile.

Inhaled glucocorticoids are also absorbed through the lung and thisroute of absorption makes a significant contribution to systemicexposure. Reduced lung absorption could therefore provide an improvedsafety profile. Studies with compound (I) have shown significantly lowerexposure to compound (I) than with fluticasone propionate after drypowder delivery to the lungs of anaesthetised pigs.

Examples of disease states in which fluticasone esters have utilityinclude inflammatory and/or allergic conditions of the nasal passagessuch as rhinitis eg seasonal and perennial rhinitis as well as otherlocal inflammatory conditions such as asthma, COPD and dermatitis.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

Preferable means for applying the formulation of the present inventionto the nasal passages is by use of a pre-compression pump. Mostpreferably, the pre-compression pump will be a VP7 model manufactured byValois SA. Such a pump is beneficial as it will ensure that theformulation is not released until a sufficient force has been applied,otherwise smaller doses may be applied. Another advantage of thepre-compression pump is that atomisation of the spray is ensured as itwill not release the formulation until the threshold pressure foreffectively atomising the spray has been achieved. Typically, the VP7model may be used with a botte capable of holding 10-50 ml of aformulation. Each spray will typically deliver 50-100 μl of such aformulation, therefore, the VP7 model is capable of providing at least100 metered doses.

A suitable dosing regime for the formulation of the present inventionwhen administered to the nose would be for the patient to inhale deeplysubsequent to the nasal cavity being cleared. During inhalation theformulation would be applied to one nostril while the other is manuallycompressed. This procedure would then be repeated for the other nostril.

Typically, one or two inhalations per nostril would be administered bythe above procedure up to three times each day, preferably once or twicedaily especially once daily.

It will be appreciated that the above dosing regime should be adjustedaccording to the patient's age, body weight and/or symptom severity.

As mentioned above, formulations comprising a fluticasone esters areuseful in human or veterinary medicine, in particular as ananti-inflammatory and anti-allergic agent.

There is thus provided as a further aspect of the invention aformulation comprising the fluticasone ester or a physiologicallyacceptable solvate thereof for use in human or veterinary medicine,particularly in the treatment of patients with inflammatory and/orallergic conditions.

According to another aspect of the invention, there is provided the useof a formulation comprising the fluticasone ester or physiologicallyacceptable solvate thereof for the manufacture of a medicament for thetreatment of patients with inflammatory and/or allergic conditions.

In a further or alternative aspect, there is provided a method for thetreatment of a human or animal subject with an inflammatory and/orallergic condition, which method comprises administering to said humanor animal subject an effective amount of a formulation comprising thefluticasone ester or physiologically acceptable solvate thereof.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

The proportion of the active fluticasone ester in the local compositionsaccording to the invention depends on the precise type of formulation tobe prepared but will generally be within the range of around 0.001-12%,more preferably 0.001 to 10% by weight. Generally, however for mosttypes of preparations advantageously the proportion used will be withinthe range of from 0.001 to 1%, more preferably 0.001-0.5, and especiallyaround 0.005 to 0.1%.

The compound of formula (I) wherein R represents furan-2-yl islong-acting, therefore preferably the compound will be deliveredonce-per-day and the dose will be selected so that the compound has atherapeutic effect in the treatment of respiratory disorders (egrhinitis) over 24 hours or more.

The pharmaceutical compositions according to the invention may also beused in combination with another therapeutically active agent, forexample, an anti-histamine or an anti-allergic. The invention thusprovides, in a further aspect, a combination comprising the fluticasoneester or a physiologically acceptable solvate thereof together withanother therapeutically active agent, for example, an anti-histamine oran anti-allergic.

Examples of anti-histamines include methapyrilene or loratadine.

Other suitable combinations include, for example, otheranti-inflammatory agents eg NSAIDs (eg sodium cromoglycate, nedocromilsodium, PDE4 inhibitors, leukotriene antagonists, iNOS inhibitors,tryptase and elastase inhibitors, beta-2 integrin antagonists andadenosine 2a agonists)) or antiinfective agents (eg antibiotics,antivirals).

Also of particular interest is use of the fluticasone ester or aphysiologically acceptable solvate thereof in combination with aphosphodiesterase 4 (PDE4) inhibitor eg cilomilast or a salt thereof.

For administration to the lung, the pharmaceutical compositionsaccording to the invention may also be used in combination with a β₂adrenoreceptor agonist. Examples of β₂-adrenoreceptor agonists includesalmeterol (eg as racemate or single enantiomer such as thes-enantiomer), salbutamol, formoterol, fenoterol or terbutaline andsalts thereof, for example the xinafoate salt of salmeterol, thesulphate salt or free base of salbutamol or the fumarate salt offormoterol. Long-acting β₂-adrenoreceptor agonists are preferred,especially those having a therapeutic effect over a 24 hour period.

Since the compounds of formula (I) are long-acting, preferably acomposition comprising the compound of formula (I) and the long-actingβ₂-adrenoreceptor agonists will be delivered once-per-day and the doseof each will be selected so that the composition has a therapeuticeffect in the treatment of respiratory disorders effect (eg in thetreatment of asthma or COPD, particularly asthma) over 24 hours or more.

Further, there is provided a process for the preparation of suchpharmaceutical compositions which comprises mixing the ingredients.

The individual compounds of such combinations may be administered eithersequentially in separate pharmaceutical compositions as well assimultaneously in combined pharmaceutical formulations. Preferablyadditional therapeutically active ingredients are dissolved in theformulation together with the fluticasone ester. Appropriate doses ofknown therapeutic agents will be readily appreciated by those skilled inthe art.

Fluticasone esters may generally be prepared following the methods ofGB2088877B and Phillips et al (1994) J Med Chem, 37, 3717-3729.

For example, a process for preparing a compound of formula (I) and otherfluticasone esters comprises alkylation of a thioacid of formula (II)

or a salt thereof.

In this process the compound of formula (II) may be reacted with acompound of formula FCH₂L wherein L represents a leaving group (eg ahalogen atom, a mesyl or tosyl group or the like) for example, anappropriate fluoromethyl halide under standard conditions. Preferably,the fluoromethyl halide reagent is bromofluoromethane. Preferably thecompound of formula (II) is employed as a salt, particularly the saltwith diisopropylethylamine.

In a preferred process for preparing the compound of formula (I), thecompound of formula (II) or a salt thereof is treated withbromofluoromethane optionally in the presence of a phase transfercatalyst. A preferred solvent is methylacetate, or more preferablyethylacetate, optionally in the presence of water. The presence of waterimproves solubility of both starting material and product and the use ofa phase transfer catalyst results in an increased rate of reaction.Examples of phase transfer catalysts that may be employed include (butare not restricted to) tetrabutylammonium bromide, tetrabutylammoniumchloride, benzyltributylammonium bromide, benzyltributylammoniumchloride, benzyltriethylammonium bromide, methyltributylammoniumchloride and methyltrioctylammonium chloride. THF has also successfullybeen employed as solvent for the reaction wherein the presence of aphase transfer catalyst again provides a significantly faster reactionrate. Preferably the product present in an organic phase is washedfirstly with aqueous acid eg dilute HCl in order to remove aminecompounds such as triethylamine and diisopropylethylamine and then withaqueous base eg sodium bicarbonate in order to remove any unreactedprecursor compound of formula (II).

Compound of formula (I) wherein R represents furan-2-yl in unsolvatedform may be prepraed by a process comprising:

-   -   (a) Crystallising the compound of formula (I) in the presence of        a non-solvating solvent such as ethanol, methanol, water, ethyl        acetate, toluene, methylisobutylketone or mixtures thereof; or    -   (b) Desolvating a compound of formula (I) in solvated form (eg        in the form of a solvate with acetone, isopropanol,        methylethylketone, DMF or tetrahydrofuran) eg by heating.

In step (b) the desolvation will generally be performed at a temperatureexceeding 50° C. preferably at a temperature exceeding 100° C. Generallyheating will be performed under vacuum.

Compound of formula (I) wherein R represents furan-2-yl has beenprepared in three crystalline polymorphic forms designated Form 1, Form2 and Form 3 which are distinguishable by their X-ray powder diffraction(XRPD) profiles. Form 3 appears to be an unstable variant of Form 2.Form 1 appears to be the thermodynamically most stable form and istherefore preferred.

A process for preparing a compound of formula (I) as unsolvated Form 1polymorph comprises dissolving compound of formula (I) inmethylisobutylketone, ethyl acetate or methyl acetate and producingcompound of formula (I) as unsolvated Form 1 by addition of anon-solvating anti-solvent such as iso-octane or toluene.

According to a first preferred embodiment of this process the compoundof formula (I) may be dissolved in ethyl acetate and compound of formula(I) as unsolvated Form 1 polymorph may be obtained by addition oftoluene as anti-solvent. In order to improve the yield, preferably theethyl acetate solution is hot and once the toluene has been added themixture is distilled to reduce the content of ethyl acetate.

According to a second preferred embodiment of this process the compoundof formula (I) may be dissolved in methylisobutylketone and compound offormula (I) as unsolvated Form 1 polymorph may be obtained by additionof isooctane as anti-solvent

Compound of formula (I) in solvated form may be prepared bycrystallising the compound of formula (I) from a solvating solvent suchas acetone or tetrahydrofuran (THF).

Compounds of formula (II) may be prepared from the corresponding17α-hydroxyl derivative of formula (III):

using for example, the methodology described by G. H. Phillipps et al.,(1994) Journal of Medicinal Chemistry, 37, 3717-3729. For example thestep typically comprises the addition of a reagent suitable forperforming the esterification eg an activated derivative of RCOOH suchas an activated ester or preferably an acid halide eg RCOOCI (employedin at least 2 times molar quantity relative to the compound of formula(III)) in the presence of an organic base eg triethylamine. The secondmole of RCOOCI reacts with the thioacid moiety in the compound offormula (III) and needs to be removed eg by reaction with an amine suchas diethylamine.

This method suffers disadvantages, however, in that the resultantcompound of formula (II) is not readily purified of contamination withthe by-product RCON(Et)₂ We have therefore invented several improvedprocesses for performing this conversion.

In a first such improved process we have discovered that by using a morepolar amine such as diethanolamine, a more water soluble by-product isobtained (in this case RCO-diethanolamide) which permits compound offormula (II) or a salt thereof to be produced in high purity since theby-product can efficiently be removed by water washing.

A process for preparing a compound of formula (II) comprises:

-   -   (a) reacting a compound of formula (III) with an activated        derivative of RCOOH as in an amount of at least 2 moles of the        activated derivative per mole of compound of formula (III) to        yield a compound of formula (IIA)        ; and    -   (b) removal of the sulphur-linked R—CO- moiety from compound of        formula (IIA) by reaction of the product of step (a) with an        organic primary or secondary amine base capable of forming a        water soluble amide.

In two particularly convenient embodiments of this process we alsoprovide methods for the efficient purification of the end product whichcomprise either

-   -   (c1) when the product of step (b) is dissolved in a        substantially water immiscible organic solvent, purifying the        compound of formula (II) by washing out the amide by-product        from step (b) with an aqueous wash, or    -   (c2) when the product of step (b) is dissolved in a water        miscible solvent, purifying the compound of formula (II) by        treating the product of step (b) with an aqueous medium so as to        precipitate out pure compound of formula (II) or a salt thereof.

In step (a) preferably the activated derivative of RCOOH may be anactivated ester of RCOOH, but is more preferably an acid halide,especially RCOOCl. A suitable solvent for this reaction is ethylacetateor methylacetate (preferably methylacetate) (when step (c1) may befollowed) or acetone (when step (c2) may be followed). Normally anorganic base eg triethylamine will be present. In step (b) preferablythe organic base is diethanolamine. The base may suitably be dissolvedin a solvent eg methanol. Generally steps (a) and (b) will be performedat reduced temperature eg between 0 and 5° C. In step (c1) the aqueouswash may be water, however the use of brine results in higher yields andis therefore preferred. In step (c2) the aqueous medium is for example adilute aqueous acid such as dilute HCl.

An alternative process for preparing a compound of formula (II)comprises:

-   -   (a) reacting a compound of formula (III) with an activated        derivative of RCOOH in an amount of at least 2 moles of        activated derivative per mole of compound of formula (III) to        yield a compound of formula (IIA); and    -   (b) removal of the sulphur-linked RCO moiety from compound of        formula (IIA) by reaction of the product of step (a) with a        further mole of compound of formula (III) to give two moles of        compound of formula (II).

In step (a) preferably the activated derivative of RCOOH may be anactivated ester of RCOOH, but is more preferably an acid halide,especially RCOOCl. A suitable solvent for his step is acetone. Normallyan organic base eg triethylamine will be present. In step (b) a suitablesolvent is DMF or dimethylacetamide. Normally an organic base egtriethylamine will be present. Generally steps (a) and (b) will beperformed at reduced temperature eg between 0 and 5° C. The product maybe isolated by treatment with acid and washing with water.

This aforementioned process is very efficient in that it does notproduce any amide by-product (thus affording inter alia environmentaladvantages) since the excess mole of ester moiety is taken up byreaction with a further mole of compound of formula (II) to form anadditional mole of compound of formula (II).

Further general conditions for the conversion of compound of formula(III) to compound of formula (II) in the two processes just describedwill be well known to persons skilled in the art.

We have found that the compound of formula (II) may advantageously beisolated in the form of a solid crystalline salt. The preferred salt isa salt formed with a base such as triethylamine,2,4,6-trimethylpyridine, diisopropylethylamine or N-ethylpiperidine.Such salt forms of compound of formula (II) are more stable, morereadily filtered and dried and can be isolated in higher purity than thefree thioacid. The most preferred salt is the salt formed withdiisopropylethylamine. The triethylamine salt is also of interest.

Compounds of formula (III) may be prepared in accordance with proceduresdescribed in GB 2088877B.

Compounds of formula (III) may also be prepared by a process comprisingthe following steps:

Step (a) comprises oxidation of a solution containing the compound offormula (V). Preferably, step (a) will be performed in the presence of asolvent comprising methanol, water, tetrahydrofuran, dioxan ordiethylene glygol dimethylether. So as to enhance yield and throughput,preferred solvents are methanol, water or tetrahydrofuran, and morepreferably are water or tetrahydrofuran, especially water andtetrahydrofuran as solvent. Dioxan and diethylene glygol dimethyletherare also preferred solvents which may optionally (and preferably) beemployed together with water. Preferably, the solvent will be present inan amount of between 3 and 10 vol relative to the amount of the startingmaterial (1 wt.), more preferably between 4 and 6 vol., especially 5vol. Preferably the oxidising agent is present in an amount of 1-9 molarequivalents relative to the amount of the starting material. Forexample, when a 50% w/w aqueous solution of periodic acid is employed,the oxidising agent may be present in an amount of between 1.1 and 10wt. relative to the amount of the starting material (1 wt.), morepreferably between 1.1 and 3 wt., especially 1.3 wt. Preferably, theoxidation step will comprise the use of a chemical oxidising agent. Morepreferably, the oxidising agent will be periodic acid or iodic acid or asalt thereof. Most preferably, the oxidising agent will be periodic acidor sodium periodate, especially periodic acid. Alternatively (or inaddition), it will also be appreciated that the oxidation step maycomprise any suitable oxidation reaction, eg one which utilises airand/or oxygen. When the oxidation reaction utilises air and/or oxygen,the solvent used in said reaction will preferably be methanol.Preferably, step (a) will involve incubating the reagents at roomtemperature or a little warmer, say around 25° C. eg for 2 hours. Thecompound of formula (IV) may be isolated by recrystallisation from thereaction mixture by addition of an anti-solvent. A suitable anti-solventfor compound of formula (IV) is water. Surprisingly we have discoveredthat it is highly desirable to control the conditions under which thecompound of formula (IV) is precipitated by addition of anti-solvent egwater. When the recrystallisation is performed using chilled water (egwater/ice mixture at a temperature of 0-5° C.) although betteranti-solvent properties may be expected we have found that thecrystalline product produced is very voluminous, resembles a soft geland is very difficult to filter. Without being limited by theory webelieve that this low density product contains a large amount ofsolvated solvent within the crystal lattice. By contrast when conditionsof around 10° C. or higher are used (eg around ambient temperature) agranular product of a sand like consistency which is very easilyfiltered is produced. Under these conditions, crystallisation typicallycommences after around 1 hour and is typically completed within a fewhours (eg 2 hours). Without being limited by theory we believe that thisgranular product contains little or no solvated solvent within thecrystal lattice.

Step (b) will typically comprise the addition of a reagent suitable forconverting a carboxylic acid to a carbothioic acid eg using hydrogensulphide gas together with a suitable coupling agent egcarbonyldiimidazole (CDI) in the presence of a suitable solvent egdimethylformamide.

The advantages of the formulation of the fluticasone esters according tothe invention may include the fact that the formulations demonstrateexcellent anti-inflammatory properties, with predictable pharmacokineticand pharmacodynamic behaviour, with an attractive side-effect profile,rapid onset of action, long duration of action, and are compatible witha convenient regime of treatment in human patients, in particular beingamendable to once-per day dosing. Further advantages may include thefact that the formulation has desirable physical and chemical propertieswhich allow for ready manufacture and storage.

DETAILED DESCRIPTION OF THE INVENTION

The following non-limiting Examples illustrate the invention:

EXAMPLES

General

¹H-nmr spectra were recorded at 400 MHz and the chemical shifts areexpressed in ppm relative to tetramethylsilane. The followingabbreviations are used to describe the multiplicities of the signals: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd(doublet of doublets), ddd (doublet of doublet of doublets), dt (doubletof triplets) and b (broad). Biotage refers to prepacked silica gelcartridges containing KP-Sil run on flash 12i chromatography module.LCMS was conducted on a Supelcosil LCABZ+PLUS column (3.3 cm×4.6 mm ID)eluting with 0.1% HCO₂H and 0.01 M ammonium acetate in water (solventA), and 0.05% HCO₂H 5% water in acetonitrile (solvent B), using thefollowing elution gradient 0-0.7 min 0% B, 0.7-4.2 min 100% B, 4.2-5.3min 0% B, 5.3-5.5 min 0% B at a flow rate of 3 ml/min. The mass spectrawere recorded on a Fisons VG Platform spectrometer using electrospraypositive and negative mode (ES+ve and ES−ve).

Intermediates

Intermediate 1: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid diisopropylethylamine salt

A stirred suspension of 6α, 9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioic acid(prepared in accordance with the procedure described in GB 2088877B)(49.5 g) in methylacetate (500 ml) is treated with triethylamine (35 ml)maintaining a reaction temperature in the range 0-5° C. 2-Furoylchloride (25 ml) is added and the mixture stirred at 0-5° C. for 1 hour.A solution of diethanolamine (52.8 g) in methanol (50 ml) is added andthe mixture stirred at 0-5° C. for at least 2 hours. Dilute hydrochloricacid (approx 1M, 550 ml) is added maintaining a reaction temperaturebelow 15° C. and the mixture stirred at 15° C. The organic phase isseparated and the aqueous phase is back extracted with methyl acetate(2×250 ml). All of the organic phases are combined, washed sequentiallywith brine (5×250ml) and treated with di-isopropylethylamine (30 ml).The reaction mixture is concentrated by distillation at atmosphericpressure to an approximate volume of 250 ml and cooled to 25-30° C.(crystallisation of the desired product normally occurs duringdistillation/subsequent cooling). Tertiary butyl methyl ether

(TBME) (500 ml) is added, the slurry further cooled and aged at 0-5° C.for at least 10 minutes. The product is filtered off, washed withchilled TBME (2×200 ml) and dried under vacuum at approximately 40-50°C. (75.3 g, 98.7%). NMR (CDCl₃) δ: 7.54-7.46 (1H, m), 7.20-7.12 (1H,dd), 7.07-6.99 (1H, dd), 6.48-6.41 (2H, m), 6.41-6.32 (1H, dd),5.51-5.28 (1H, dddd²J_(H-F) 50 Hz), 4.45-4.33(1H, bd), 3.92-3.73 (3H,bm), 3.27-3.14 (2H, q), 2.64-2.12 (5H, m), 1.88-1.71 (2H, m), 1.58-1.15(3H, s), 1.50-1.38 (15H, m), 1.32-1.23 (1H, m), 1.23-1.15 (3H s),1.09-0.99 (3H, d)

Intermediate 2: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester Unsolvated Form 1

A mobile suspension of Intermediate 1 (12.61 g, 19.8 mmol) in ethylacetate (230 ml) and water (50 ml) is treated with a phase transfercatalyst (benzyltributylammonium chloride, 10 mol %), cooled to 3° C.and treated with bromofluoromethane (1.10 ml, 19.5 mmol, 0.98equivalents), washing in with prechilled (0° C.) ethyl acetate (EtOAc)(20 ml). The suspension is stirred overnight, allowing to warm to 17° C.The aqueous layer is separated and the organic phase is sequentiallywashed with 1M HCl (50 ml), 1% w/v NaHCO₃ solution (3×50 ml) and water(2×50 ml). The ethylacetate solution is distilled at atmosphericpressure until the distillate reaches a temperature of approximately 73°C. at which point toluene (150 ml) is added. Distillation is continuedat atmospheric pressure until all remaining EtOAc has been removed(approximate distillate temperature 103° C.). The resultant suspensionis cooled and aged at <10° C. and filtered off. The bed is washed withtoluene (2×30 ml) and the product oven dried under vacuum at 60° C. toconstant weight to yield the title compound (8.77 g, 82%) LCMS retentiontime 3.66 min, m/z 539 MH⁺, NMR δ(CDCl₃) includes 7.60 (1H, m),7.18-7.11 (2H, m), 6.52 (1H, dd, J 4.2 Hz), 6.46 (1H, s), 6.41 (1H, dd,J 10, 2 Hz), 5.95 and 5.82 (2H dd, J 51, 9 Hz), 5.48 and 5.35 (1H, 2m),4.48 (1H, m), 3.48 (1H, m), 1.55 (3H, s), 1.16 (3H, s), 1.06 (3H, d, J 7Hz).

Pharmacological Activity

In Vitro Pharmacological Activity

Pharmacological activity was assessed in a functional in vitro assay ofglucocorticoid agonist activity which is generally predictive ofanti-inflammatory or anti-allergic activity in vivo.

For the experiments in this section, compound of formula (I) was used asunsolvated Form 1 (Intermediate 2)

The functional assay was based on that described by K. P. Ray et al.,Biochem J. (1997), 328, 707-715. A549 cells stably transfected with areporter gene containing the NF-κB responsive elements from the ELAMgene promoter coupled to sPAP (secreted alkaline phosphatase) weretreated with test compounds at appropriate doses for 1 hour at 37° C.The cells were then stimulated with tumour necrosis factor (TNF, 10ng/ml) for 16 hours, at which time the amount of alkaline phosphataseproduced is measured by a standard colourimetric assay. Dose responsecurves were constructed from which EC₅₀ values were estimated.

In this test the compound of formula (I) showed an EC₅₀ value of <1 nM.

The glucocorticoid receptor (GR) can function in at least two distinctmechanisms, by upregulating gene expression through the direct bindingof GR to specific sequences in gene promotors, and by downregulatinggene expression that is being driven by other transcription factors(such as NFκB or AP-1) through their direct interaction with GR.

In a variant of the above method, to monitor these functions, tworeporter plasmids have been generated and introduced separately intoA549 human lung epithelial cells by transfection. The first cell linecontains the firefly luciferase reporter gene under the control of asynthetic promoter that specifically responds to activation of thetranscription factor NFκB when stimulated with TNFα. The second cellline contains the renilla luciferase reporter gene under the control ofa synthetic promotor that comprises 3 copies of the consensusglucocorticoid response element, and which responds to directstimulation by glucocorticoids. Simultaneous measurement oftransactivation and transrepression was conducted by mixing the two celllines in a 1:1 ratio in 96 well plate (40,000 cells per well) andgrowing overnight at 37° C. Test compounds were dissolved in DMSO, andadded to the cells at a final DMSO concentration of 0.7%. Afterincubation for 1 h 0.5 ng/ml TNFα (R&D Systems) was added and after afurther 15 hours at 37° C., the levels of firefly and renilla luciferasewere measured using the Packard Firelite kit following themanufacturers' directions. Dose response curves were constructed fromwhich EC₅₀ values were determined. Transactivation Transrepression (GR)ED₅₀ (nM) (NFκB) ED₅₀ (nM) Compound of Formula (I) 0.06 0.20 Metabolite(X) >250 >1000 Fluticasone propionate 0.07 0.16In Vivo Pharmacological Activity

Pharmacological activity in vivo was assessed in an ovalbumin sensitisedBrown Norway rat eosinophilia model. This model is designed to mimicallergen induced lung eosinophilia, a major component of lunginflammation in asthma.

For the experiments in this section, compound of formula (I) was used asunsolvated Form 1.

Compound of formula (I) produced dose dependant inhibition of lungeosinophilia in this model after dosing as an intra-tracheal (IT)suspension in saline 30 min prior to ovalbumin challenge. Significantinhibition is achieved after a single dose of 30 μg of compound offormula (I) and the response was significantly (p=0.016) greater thanthat seen with an equivalent dose of fluticasone propionate in the samestudy (69% inhibition with compound of formula (I) vs 41% inhibitionwith fluticasone propionate).

In a rat model of thymus involution 3 daily IT doses of 100 μg ofcompound (I) induced significantly smaller reductions in thymus weight(p=0.004) than an equivalent dose of fluticasone propionate in the samestudy (67% reduction of thymus weight with compound (I) vs 78% reductionwith fluticasone propionate).

Taken together these results indicate a superior therapeutic index forcompound (I) compared to fluticasone propionate.

In Vitro Metabolism in Rat and Human Hepatocytes

Incubation of compound (I) with rat or human hepatocytes shows thecompound to be metabolised in an identical manner to fluticasonepropionate with the 17-β carboxylic acid (X) being the only significantmetabolite produced. Investigation of the rate of appearance of thismetabolite on incubation of compound (I) with human hepatocytes (37° C.,10 μM drug concentration, hepatocytes from 3 subjects, 0.2 and 0.7million cells/mL) shows compound (I) to be metabolised ca. 5-fold morerapidly than fluticasone propionate: 17-β acid metabolite production(pmol/h) Subject Cell density Fluticasone number (million cells/mL)Compound (I) propionate 1 0.2 48.9 18.8 1 0.7 73.3 35.4 2 0.2 118 9.7 20.7 903 23.7 3 0.2 102 6.6 3 0.7 580 23.9

Median metabolite production 102-118 pmol/h for compound (I) and18.8-23.0 pmol/h for fluticasone propionate.

Pharmacokinetics after Intravenous (IV) and Oral Dosing in Rats

Compound (I) was dosed orally (0.1 mg/kg) and IV (0.1 mg/kg) to maleWistar Han rats and pharmacokinetic parameters determined. Compound (I)showed negligible oral bioavailability (0.9%) and plasma clearance of47.3 mL/min/kg, approaching liver blood flow (plasma clearance offluticasone propionate=45.2 mL/min/kg).

Pharmacokinetics after Intra-tracheal Dry Powder Dosing in the Pig.

Anaesthetised pigs (2) were dosed intra-tracheally with a homogenousmixture of compound (I) (1 mg) and fluticasone propionate (1 mg) as adry powder blend in lactose (10% w/w). Serial blood samples were takenfor up to 8 h following dosing. Plasma levels of compound (I) andfluticasone propionate were determined following extraction and analysisusing LC-MS/MS methodology, the lower limits of quantitation of themethods were 10 and 20 pg/mL for compound (I) and fluticasone propionaterespectively. Using these methods compound (I) was quantifiable up to 2hours after dosing and fluticasone propionate was quantifiable up to 8hours after dosing. Maximum plasma concentrations were observed for bothcompounds within 15 min after dosing. Plasma half-life data obtainedfrom IV dosing (0.1 mg/kg) was used to calculate AUC (0-inf) values forcompound (I). This compensates for the plasma profile of Compound (I)only being defined up to 2 hours after an IT dose and removes any biasdue to limited data between compound (I) and fluticasone propionate.

C_(max) and AUC (0-inf) values show markedly reduced systemic exposureto compound (I) compared to fluticasone propionate: AUC (0-inf) Cmax(pg/mL) (hr · pg/mL) Pig 1 Pig 2 Pig 1 Pig 2 Compound of Formula (I) 117 81 254 221 Fluticasone propionate 277 218 455 495

The pharmacokinetic parameters for both compound (I) and fluticasonepropionate were the same in the anaesthetised pig following intravenousadministration of a mixture of the two compounds at 0.1 mg/kg. Theclearance of these two glucocorticoids is similar is this experimentalpig model.

EXAMPLES Example 1

Nasal Formulation Containing 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

A formulation for intranasal delivery was prepared with ingredients asfollows: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester 0.005% w/w Tyloxapol    2% w/w dextrose    5%w/w BKC 0.015% w/w EDTA 0.015% w/w water to 100%in a total amount suitable for 120 actuations and the formulation wasfilled into a bottle (plastic or glass) fitted with a metering valveadapted to dispense 50 or 100 μl per actuation

The device was fitted into a nasal actuator (Valois, e.g. VP3, VP7 orVP7D)

The formulation was prepared as follows:

The surfactant Tyloxapol was first heated to 60-70° C. to lower itsviscosity. Intermediate 2 was then added very slowly while stirringusing a suitable propellor mixer, while the surfactant was still hot.Separately, approximately 80% remaining quantity of water was heatedsimilarly to 60-70° C., and dextrose dissolved completely using apropellor mixer. This solution, while still hot, was added very slowlyto the drug/Tyloxapol solution while stirring. This preparation wasallowed to continue mixing for a minimum of 30 min, or until all drugwas observed to dissolve completely. In the remaining water, BKC andEDTA were dissolved and then added slowly to the final formulation,which was further mixed until clear. If still necessary, the formulationwas brought to its final weight with water alone. The pH was determined,and adjusted to pH 6.5 if necessary.

Similarly prepared were other formulations as follows:

Example 2

Nasal Formulation Containing 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester

A formulation for intranasal delivery was prepared with ingredients asfollows: 6α,9α-Difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester 0.05% w/w Triton X-100    5% w/w Dextrose   4% w/w BKC 0.015% w/w EDTA 0.015% w/w water to 100%in a total amount suitable for 120 actuations and the formulation wasfilled into a bottle fitted with a metering valve adapted to dispense 50or 100 μl per actuation. The device was fitted into a nasal actuator(Valois).

Example 3

Nasal Formulation Containing Fluticasone Propionate

A formulation for intranasal delivery was prepared with ingredients asfollows: Fluticasone propionate  0.05% w/w Triton X-100    5% w/wDextrose    4% w/w BKC 0.015% w/w EDTA 0.015% w/w water to 100%in a total amount suitable for 120 actuations and the formulation wasfilled into a bottle fitted with a metering valve adapted to dispense 50or 100 μl per actuation.

Example 4

Nasal Formulation Containing Fluticasone Propionate

A formulation for intranasal delivery was prepared with ingredients asfollows: Fluticasone propionate  0.05% w/w Tyloxapol    5% w/w dextrose   5% w/w BKC 0.015% w/w EDTA 0.015% w/w water to 100%in a total amount suitable for 120 actuations and the formulation wasfilled into a bottle fitted with a metering valve adapted to dispense 50or 100 μl per actuation The device was fitted into a nasal actuator(Valois).Stability Testing

The chemical stability of Examples 1 and 2 was tested by placing samplesat 5, 25 and 40° C. for a period 4 weeks and sampled as necessary.Analysis of the samples for drug content was done by HPLC. Drug amountEDTA BKC Example Condition (% label) (% w/w) (% w/w) pH Example 1Initial 97.1 0.0151 0.0146 6.70 (97.0) 25° C./60% RH 94.2 0.0149 0.01446.20 (95.6) 40° C./75% RH 92.3 0.0145 0.0150 5.82 (99.8) Example 2Initial 100.4 0.0157 0.0161 6.52 (107.3) 25° C./60% RH 96.4 0.01510.0135 5.93 (90.3) 40° C./75% RH 95.4 0.0149 0.0144 5.40 (96.1)

The data suggests that the examples were stable for a period of 1 monthat accelerated conditions.

Throughout the specification and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The patents and patent applications described in this application areherein incorporated by reference.

1. A pharmaceutical formulation comprising an aqueous carrier liquidhaving dissolved therein (a) a glucocorticoid of formula (I)

wherein R represents a 5 membered heterocyclic aromatic ring containing1 to 3 heteroatoms selected from O, N and S, optionally substituted byone or more methyl or halogen atoms or a solvate thereof, as amedicament; and (b) a solubilising agent for assisting thesolubilisation of the medicament in the aqueous carrier liquid.
 2. Apharmaceutical formulation according to claim 1 wherein the solubilisingagent is a surfactant.
 3. A pharmaceutical formulation according toclaim 2 wherein the surfactant is selected from the group consisting ofaα-[4-(1,1,3,3-tetramethylbutyl)phenyl]-ω-hydroxypoly(oxy-1,2-ethanediyl)polymer and a 4-(1,1,3,3-Tetramethylbutyl)phenol polymer withformaldehyde and oxirane.
 4. A pharmaceutical formulation according toclaim 3 wherein the surfactant is a 4-(1,1,3,3-Tetramethylbutyl)phenolpolymer with formaldehyde and oxirane.
 5. A pharmaceutical formulationaccording to claim 2 which further has dissolved therein a hydroxycontaining organic co-solvating agent or phosphatidyl choline.
 6. Apharmaceutical formulation according to claim 5 wherein the hydroxycontaining organic co-solvating agent is dextrose.
 7. A pharmaceuticalformulation according to claim 1 wherein the formulation furthercomprises chloride as an isotonic agent.
 8. A pharmaceutical formulationaccording to claim 1 which comprises another therapeutically activeagent.
 9. A pharmaceutical formulation according to claim 8 wherein theother therapeutically active agent is an anti-histamine or ananti-allergic.
 10. A container containing a pharmaceutical formulationaccording to claim 1, fitted with a metering valve.
 11. A device adaptedfor intranasal delivery of a pharmaceutical formulation comprising acontainer according to claim
 10. 12. A method of treatment ofinflammatory and/or allergic conditions of the nasal passages whichcomprises administering to the nose a pharmaceutical formulationaccording to claim
 1. 13. The method according to claim 12 wherein theadministration is once-per-day.
 14. A process for preparing apharmaceutical formulation which comprises: (a) providing: (i) aglucocorticoid of formula (I)

wherein R represents a 5 membered heterocyclic aromatic ring containing1 to 3 heteroatoms selected from O, N and S, optionally substituted byone or more methyl or halogen atoms or a solvate thereof, as amedicament; (ii) water and (iii) a solubilizing agent for assisting thesolubilization of the medicament in the aqueous carrier liquid, whereinsaid solubilizing agent is a surfactant; (b) dissolving theglucocorticoid of formula (I) in the undiluted surfactant at atemperature of at least 60° C., to form a mixture of glucocorticoid andsurfactant; (c) heating said water to a temperature of at least 60° C.,and combining said heated water to said mixture of glucocorticoid andsurfactant to achieve the desired concentration of active ingredient;(d) optionally modifying the pH of the final solution; (e) filtering thehot solution comprising of water, surfactant and medicament to removeany residual particulate matter.